Noroviruses (NoVs) are a group of single-stranded, positive sense RNA viruses constituting the Norovirus genus in the family Caliciviridae. NoVs have been recognized as the most important cause of viral epidemic acute gastroenteritis affecting people of all ages [1,2]. In the United States NoVs cause 23 million infections each year and are responsible for more than 90% of the outbreaks of viral gastroenteritis. On a worldwide basis NoVs lead to 218,000 deaths in developing countries and 1.1 million episode of pediatric gastroenteritis in developed countries annually [3]. Thus, NoV associated diseases have been a heavy burden to public healthcare. NoVs are difficult to control owing to their widespread nature and the lack of effective vaccines and antivirals.
NoVs are small (about 38 nm in diameter), non-enveloped, single-stranded, and positive-sense RNA viruses belonging to the family Caliciviridae. The NoV genome encodes three open reading frames (ORF) in which ORF-2 encodes one major structure protein of about 60 kDa that spontaneously forms virus-like particles (VLPs) when expressed in baculovirus or in other expression systems. These VLPs are morphologically and antigenically indistinguishable from the native forms of viruses found in human stools, providing valuable materials for development of immunological assays, for study of virus-host interaction, as a candidate vaccine, and for determination of the structure and capsid assembling of NoVs.
NoVs are known to recognize human histo-blood group antigens (HBGAs) as receptors. HBGAs are complex carbohydrates linked to glycoproteins or glycolipids that are present on the surfaces of red blood cells and mucosal epithelial cells or as free oligosaccharides in biological fluids such as blood, saliva, milk, and intestinal contents. The HBGA system is controlled by multiple gene families that contain silent alleles, and three major HBGA families, the Lewis, secretor, and ABO families, are involved in NoV infection. The recognition of HBGAs by NoVs has been found to be highly specific; different NoVs recognize different HBGAs, and so far eight distinct receptor-binding patterns have been identified. According to potentially shared antigenic epitopes among different NoVs (the A, B, H and Lewis epitopes), the eight binding patterns can be sorted into two groups: the A/B and the Lewis (non-secretor) binding groups. Strains in the A/B binding groups bind to the A and/or B or H epitopes but not the Lewis epitopes, while strains in the Lewis binding group recognize the Lewis and H epitopes but not the A and B epitopes.
The association of HBGAs with NoV infection has been demonstrated by human volunteer studies wherein the attachment of NoV to the intestinal epithelium via a matched HBGA receptor is a prerequisite for NoV infection. Inhibition of this interaction may result in prevention or control of the viral infection.
Currently there is no effective intervention available against NoV gastroenteritis. The present disclosure addresses the long felt need for compounds useful in the prevention and/or treatment of NoV infection.